Testicular germ cell tumors (TGCT) are the most common cancers in young men. Several striking features characterize the epidemiology of TGCT: increasing incidence, racial disparity in risk and high familial relative risks. However, knowledge of TGCT risk factors and causes lags far behind that of other malignancies. Recently, genome-wide association (GWA) studies have identified six loci associated with TGCT susceptibility, the most striking being KITLG with a per allele risk surpassing 3- fold. However, these six loci only explain 11% of the risk to brothers of men with TGCT. In conjunction with our preliminary data, we hypothesize that additional TGCT risk loci can be identified. In Specific Aim 1, we propose a pooled analysis of all existing genome-wide association (GWA) studies of TGCT, including 2227 cases and 6762 controls, to discover novel genetic markers of risk not identified in the individual studies. The top 2000 SNPs along with 500 from resequencing of known risk loci will be taken into replication into 5491 TGCT cases and 8190 controls from a new international TGCT consortium representing 21 sites in eight countries. In Specific Aim 2, we will further characterize genomic regions containing risk markers noted in replication through deep resequencing. SNP markers identified by resequencing and representing putative causal variant(s) also will be tested for association in the replication samples. In Specific Aim 3, we will examine whether replicated TGCT risk alleles affect risk of TGCT through maternal and/or parent-of-origin effects. As the development of TGCT begins in utero, it may involve factors derived from the pregnancy environment. In addition, evidence from mouse models of TGCT susceptibility and our preliminary data support parent-of-origin effects. To address this aim, genotype data on 1878 case-parent triads and 895 case-parent dyads will be analyzed using a log-linear method to assess the independent relative risks associated with maternal genotypes and maternal vs. parental allele transmission, adjusted for offspring genotype. Finally, Aim 4 focuses on the establishment of a TGCT consortium and formalizes the research alliance brought together for this application. Together, these aims will significantly advance our current understanding of the genetic basis and biological underpinnings of TGCT. PUBLIC HEALTH RELEVANCE: The results of this project will provide new information on the contribution of risk alleles to the etiology of TGCT. Knowledge gained also will serve to heighten our understanding of the underlying biology of TGCT and its related conditions. We expect that ultimately this information may provide for novel advances in determining risk assessment for this early onset cancer.